tbuckley/cabot-search huggingface dataset:
A phase 1b study to evaluate the efficacy, safety, and pharmacokinetics of an investigational microbiome therapeutic, SER-155, in adults undergoing hematopoietic stem cell transplantation.
Authors: Doris M. Ponce, Satyajit Kosuri, Nandita Khera, Zachariah Michael DeFilipp, Mary-Jane Lombardo, Christopher B. Ford, Jonathan U. Peled, Marcel R. M. Van Den Brink, Lisa von Moltke, Bindu Tejura
Journal: Journal of Clinical Oncology (2023)

TPS7080 Background: In patients undergoing allogeneic hematopoietic cell transplantation (HCT), loss of gastrointestinal microbial diversity is associated with risk of bloodstream infections (BSI), acute graft-versus-host disease (aGvHD), and death. SER-155 is a rationally designed investigational cultivated microbiome therapeutic, hypothesized to improve clinical outcomes in HCT by restoring colonization resistance to potential pathogens, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a Phase 1b study evaluating the efficacy, safety, and pharmacokinetics (PK) of SER-155 in adults undergoing HCT. Methods: This study will enroll approximately 70 subjects ≥18 years in an open-label Cohort 1 (n = 10) followed by a double-blind, placebo-controlled Cohort 2 (n = 60) randomized 1:1 to SER-155 or placebo. A variety of conditioning regimens, donor types, and GVHD-prophylaxis regimens are included. Exclusion criteria include history of severe colitis or active inflammatory bowel disease or total colectomy, umbilical cord blood or ex vivo T-cell depletion, exposure to fecal microbiota transplant or any live microbial therapeutic within 3 months prior to screening, and evidence of relapse or progression of hematologic malignancy (minimal residual disease is allowed). Following screening, participants in both cohorts receive 2 treatment courses (one before and one after HCT), each comprised of microbiome conditioning with oral vancomycin or placebo followed by SER-155 or placebo, plus a conditional 3rd treatment course if the subject receives antibiotics. Safety outcomes are followed through 52 weeks post HCT. The primary endpoint is the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints include rates of BSI, gastrointestinal infections, aGvHD, febrile neutropenia and overall survival. Microbiome related endpoints include engraftment of SER-155 bacterial strains in the gastrointestinal tract (PK endpoint) and fecal microbiome diversity, composition and metabolites. Results: Cohort 1 enrollment is complete, with 13 participants receiving SER-155. In December 2022, the Data and Safety Monitoring Committee supported continuation to Cohort 2 enrollment following review of safety data from Cohort 1. Enrollment in Cohort 2 is underway. Conclusions: This Phase 1b study is designed to assess the safety, and clinical efficacy of SER-155 in allogeneic HCT, expanding the clinical experience of microbiome- directed interventions in allogeneic HCT recipients. Clinical trial information: NCT04995653 .
Treg cells and the response to neoadjuvant chemotherapy combined with immunotherapy in resectable esophageal squamous carcinoma.
Authors: Bo Jiang, Xin Yang, Pengyi Yu, Chu Zhang, Chunyang Li, Wenhua Tang, Junling Zhang, Mengli Huang
Journal: Journal of Clinical Oncology (2023)

e14626 Background: More and more studies focus on the neoadjuvant chemotherapy combined with immunotherapy (chemo-immunotherapy) in resectable esophageal squamous carcinoma (ESCC). Herein, we aimed to evaluate the efficacy and safety of neoadjuvant programmed cell death protein 1 inhibitors with chemotherapy and explore tumor microenvironment (TME) profiles. Methods: Patients with previously untreated, resectable, stage III ESCC in the third affiliated hospital of Soochow University were enrolled. Each patient received two-four cycles of neoadjuvant chemo-immunotherapy before surgical resection. The TME profiles of formalin-fixed paraffin-embedded tumor samples at baseline were evaluated by multiplex immunofluorescence to discover novel biomarkers of response to neoadjuvant chemo-immunotherapy. Results: Twenty patients were included, all of whom underwent R0 resection. 85% (17/20) of patients underwent 2 cycles of neoadjuvant therapy. TP53 (13/20,65%) was were high-frequency mutated gene, followed by CDKN2A (5/20,25.0%) and PIK3CA (3/20, 15.0%). PD-L1 positive (TPS≥1%) was found in only 3 patients. Postoperative pathological evaluation showed that 18 patients (90.0%) were major pathologic response (MPR), of which 5 patients (28.0%) achieved pathological complete response (pCR). Neoadjuvant therapy has acceptable side effects. TME profiles at baseline showed no significant correlation between PD-L1 and pathological response. The density of Treg cell in the tumor area was significantly lower in pCR patients than in MPR patients (P=0.0302). Conclusions: Neoadjuvant chemo-immunotherapy was well tolerated and was effective therapy for resectable ESCC. Treg cells may serve as potential predictive biomarkers.
Relationship between efficacy of phase I/II drug ispinesib in medulloblastoma, molecular subtypes, and p53-mutant status.
Authors: Wan-Yee Teo, Shiying Huang, Yuchen Du, Angela Major, Jack M. Su, Kam Man Hui, M. Tarek Elghetany, Xiao-Nan Li
Journal: Journal of Clinical Oncology (2023)

e14001 Background: KIF11, a mitotic kinesin, is responsible for assembly and maintenance of mitotic spindle during mitosis. Tumor cells can upregulate KIF11 to enhance tumor proliferation. Many cancers overexpress KIF11, including medulloblastoma (MB), the most common malignant brain tumor in children. MB is molecularly classified into 4 molecular subtypes: sonic-hedgehog (SHH)-activated MB, Wingless (WNT)-activated, and less characterized Group 3 and 4 subtypes. Group 3 and 4 MBs are the most aggressive subtypes and Group 3 MBs have the worst survival outcome. p53 mutation defines a high-risk group in MB patients. We evaluated the efficacy of a Phase I/II KIF11 inhibitor, ispinesib on MB. Methods: We employed in-vitro proliferation assays (CCK), flow cytometry (Annexin V, Propidium Iodide), western blot, Hoechst staining, and two patient-derived orthotopic xenograft (PDOX) mouse models for in-vivo drug testing. Results: Ispinesib effectively inhibited proliferation at nanomolar concentrations for all 5 MB cell lines. A comparison of IC 50 (day 4) indicated that p53-mutational-status did not influence sensitivity to ispinesib. In all five cell lines, regardless of p53 mutational status, ispinesib led to G2/M arrest. However, different p53-mutational-status led to different modes of cell death. High levels of necrotic cell death were observed in p53-mutant, while apoptosis was the predominant mode of cell death in p53-wildtype, on flow cytometry. Apoptotic nuclei were more significantly observed in p53-wildtype (p = 0.002) while p53-mutant cell line demonstrated more micronuclei (p = 0.0302) and multi-nucleation (p= 0.0161), compared to respective DMSO-control cells on Hoechst staining. Ispinesib has demonstrated effective blood brain barrier penetration in brain xenografts. We compared 2 PDOX models of MB. Ispinesib significantly improved survival outcome of Group 3 MB (Control=6, Treated=7, Log-rank p=0.0003), but worsened the survival outcome of p53-mutant SHH MB (Control=14, Treated=11, Log-rank p=0.169). This differential efficacy of ispinesib was recapitulated in the matched 3D-neurosphere cultures of both PDOX models. Cancer-stem-cell (CSC)-enriched neurospheres derived from aggressive Group 3 subtype demonstrated susceptibility to 7-day in-vitro treatment with ispinesib (AUC=0.7743). Monolayer tumor cells demonstrated similar susceptibility (AUC=0.7757). Area under curve (AUC)&gt;0.7 was the significant cut-off. In contrast, both CSC-enriched neurospheres (AUC=0.379) and monolayer tumor cells (AUC=0.491) derived from p53-mutant SHH MB did not demonstrate susceptibility to ispinesib, consistent with matching PDOX models. Conclusions: Preclinically, our results indicate feasibility of ispinesib treatment in MB, specifically aggressive Group 3 MB. Importantly, p53-mutant SHH MB represents a poor molecular-subtype candidate for ispinesib therapy.
Effect of fecal transplantation on patients’ reported outcome after immune checkpoint inhibitor colitis.
Authors: Yinghong Wang, Krishnavathana Varatharajalu, Malek Shatila, Shu-En Shen, Mary Herrera, Elizabeth Gonzalez, Xin Shelley Wang, Anusha Thomas, Zhi-Dong Jiang, Herbert L. DuPont
Journal: Journal of Clinical Oncology (2023)

2645 Background: The use of fecal microbiota transplantation (FMT) has traditionally been reserved for the treatment of recurrent Clostridioides difficile infections (CDI). As the gut microbiome has been increasingly acknowledged to play a role in a variety of bodily processes, FMT has seen its application extended to other gastrointestinal disorders. Immune-mediated colitis (IMC) is a similar entity to inflammatory bowel disease and arises as a side effect of immune checkpoint inhibitor therapy to stimulate the immune response. Treatment of IMC is mostly limited to immunosuppressants e.g. corticosteroids, infliximab, and vedolizumab. Cases refractory to such medications pose a significant challenge. FMT has been shown to be a successful treatment in refractory IMC in small case series, further large studies are needed to determine its efficacy. Methods: We measured the efficacy of FMT for refractory IMC among 47 patients via chart review and clinical assessment and patients’ reported outcome (PRO) via established MD Anderson Symptom Inventory (MDASI). Among them, 9 patients had concurrent CDI as well at the time of diagnosis. Results: Forty-seven patients were included in our study. Most patients had a peak diarrhea grade ≥ 3 (93.6%) and colitis grade ≥ 2 (91.5%). Ulcerous (23, 49.0%) and non-ulcerous (12, 25.5%) inflammation were the predominant endoscopic findings. 45 (95.7%) patients received corticosteroids, and 43 patients (91.5%) received add-on infliximab or vedolizumab. IMC symptom response was 85.1% after FMT with median time to response of 4.5 days. The transient complications rate is 34.0% at 7 days and 17.0% at 30 days. Response rate among the 38 patients without concurrent CDI was 86.8%. Forty-one (87.2%) patients demonstrated clinical remission by the end of the study period. On the PRO analysis, we observed a favorable trend of significant patient-reported symptom reduction on diarrhea during 12 weeks after FMT, along with improved daily physical functioning on working. Conclusions: FMT may serve as a potential treatment option in IMC refractory to standard treatment to avoid long-term steroid dependency and immunosuppression. It is effective to maintain IMC remission with a low complication rate. The role of the gut microbiome in cancer and the implications for FMT remain uncertain and need further elucidation. Clinical trial information: NCT03819296 . [Table: see text]
Why adult patients with acute leukemias are dying in the developing world: The other side of the coin.
Authors: Astghik Voskanyan, Arusyak Ivanyan, Lusine Harutyunyan, Alisa Movsisyan, Nerses Ghahramanyan, Lusine Sahakyan, Samvel Danielyan, Gevorg Tamamyan
Journal: Journal of Clinical Oncology (2023)

e19035 Background: Majority of the patients with acute leukemias can reach complete remission (CR) in case of appropriate therapy and many of those in CR are expected to remain in remission for several years, which could be considered a cure. Because of progress in recent decades, less and less patients in the developed world are dying. In the developing world the situation is different and with the current work we would like to report the state of leukemias in Armenia and significant disparities, which affect the treatment outcomes of those patients. Methods: We analyzed the medical records of all expired adult patients diagnosed with acute leukemia at the Hematology Center of Armenia from 01/01/2016 until 12/31/2020. Hematology Center is the only institution in Armenia treating leukemias, meaning the data is a countrywide report. Death dates were taken from the United Information System of Electronic Healthcare in the Republic of Armenia. Results: Over the five-year period, 431 patients were diagnosed with AL, of which 310 (71.9%) died. 244 medical records were available for further analysis. The median age of patients at the time of diagnosis was 59 (18-85), 45.9% (112) were female. 23.8% (58) of patients died before starting chemotherapy, of which 44.8% (26) refused the treatment, the others died from different complications due to disease progression. 33.6% (82) patients reached CR of which 29.3% (24) died in first remission: 3 pts from acute heart failure, 1 from COVID-19, 3 from septic shock, 1 from pulmonary aspergillosis, 2 from acute respiratory failure, in 14 patients the causes of death were unknown. 58(70.7%) of those patients, who developed relapse, only 12% (7) of them reached 2nd remission. In 82.8% (48) of patients the death was because of disease progression. One patient died from acute kidney failure, 1 from acute respiratory failure, 1 from COVID-19,1 from septic shock. 50 patients died during induction therapy, form which 58% (29) was due to disease progression, the other reasons were: septic shock, acute heart failure, brain hemorrhage, acute respiratory failure, mesenteric venous thrombosis, multiple organ failure. 30 patients were resistant to the first line therapy and refused further therapy. In 24 patients it was not possible to clarify if they have developed remission and what were the death causes. Conclusions: In our analyzed cohort 23% of all patients refused the treatment, almost half of which did not even start the treatment. It should also be mentioned that because of stigma about cancer, some of those patients did not know their diagnosis and the decisions were made by the relatives. Other reasons for such high abandonment rates are mostly financial and social.
The impact of HPV vaccination in Florida compared to New York.
Authors: Thanuja Neerukonda, Neeharika Srivastava Makani, Dhruv Patel
Journal: Journal of Clinical Oncology (2023)

10544 Background: HPV is responsible for cancers including anus, penis, vulvovaginal, and oropharyngeal but cervical cancer is the most common cancer caused by HPV. To study the impact of HPV vaccination, we compared age-adjusted cervical cancer incidence and death rates in New York, a state with a high HPV vaccination rate, to Florida, a state with a lower vaccination rate, prior to HPV vaccination and 10 years post HPV vaccination availability. Methods: This is an ecologic study observing the cervical cancer incidence and death rates prior to (2005) and after (2016) the introduction of the HPV vaccination using state wide healthcare cancer registries. Results: The HPV vaccine became available in the United States in 2006. Historically, Florida was found to have a low HPV vaccination rate in 2009 with less than 40% compared to New York which had a high rate of 50% in 2009. By 2016, Florida’s HPV vaccination rate improved to 55% but was still low compared to New York with a rate greater than 70%. New York had a decline of cervical cancer incidence of 9.7 per 100,000 in 2005 to 8.3 in 2016. New York had a decrease in death rate from 3.0 in 2005 to 2.7 in 2016. In Florida, the cervical cancer incidence rate from 2005 to 2016 increased from 9.7 to 9.9 and the mortality was 3.0 in 2005 and 2.9 in 2016. When comparing New York’s cervical cancer incidence rates, there was a statistically significant drop in age-adjusted incidence before HPV-vaccination compared to 10 years post vaccination availability. When analyzing cervical cancer incidence in 2016, significant increase in cases between Florida’s incidence compared to New York’s. Conclusions: Since the introduction of the HPV vaccination, age-adjusted incidence rate of cervical cancer has declined in New York but not in Florida. This may be due to lagging HPV vaccination rates in Florida in addition to other sociodemographic or healthcare factors. There has been minimal change in cervical cancer death rates between both states, likely attributed by the low death rate associated with cervical cancer. The medical community needs to work together to address the barriers to HPV vaccination and promote programs to increase vaccination rates which will reduce the incidence and mortality of cervical, anus, penis, vagina, vulva, and oropharyngeal cancer. [Table: see text]
Outcomes of different therapies in acute myeloid leukemia patients with core-binding factor.
Authors: Yile Zhou, Huafeng Wang, Jie Jin
Journal: Journal of Clinical Oncology (2023)

e19036 Background: Acute myeloid leukemia (AML) with RUNX1:RUNXT1 fusion or CBFB:MYH11 fusion is defined as core-binding factor AML (CBF-AML) and has been considered to show favorable prognosis. Methods: We conducted a retrospective analysis on previously untreated CBF-AML patients who received standard-dose induction therapies between Jan 2018 and Dec 2020 in our medical center. Patients were classified into 5 groups based on the induction regimens: VA, DA, IA, HAA, and DAV. The dosage of these regimens were determined as follows: VA, venetoclax 100mg d1,200mg d2, 400mg d3-28, Azacytidine 75mg/m 2 d1-7; DA, daunorubicin 60mg/m 2 d1-3, cytarabine 100mg/m 2 d1-7; idarubicin 8-10mg/m 2 d1-3, cytarabine 100mg/m 2 d1-7; HAA, homoharringtonine 2mg/m 2 d1-7, cytarabine 100mg/m 2 d1-7, aclarubicin 12mg/m 2 d1-7; DAV, daunorubicin 60mg/m 2 d1-3, cytarabine 100mg/m 2 d1-7, venetoclax 100mg d4, 200mg d5, 400mg d6-11. The response rate and survival data were analysed between these groups. Results: There’s a total of 106 CBF-AML patients involved, 85(80.2%) with RUNX1:RUNXT1 fusion and 21(19.8%) with CBFB:MYH11 fusion. The most common concomitant mutation was KIT (33%), and the most frequent hotspot mutation site was D816V in exon 17. The median age was 46 years ranging from 7 to 78, and 46.2% of the patients were male.Patients were classified into 5 groups based on the induction regimens, and there were 9 in VA group, 21 in HAA group, 23 in DA group, 38 in IA group, and 15 in DAV group. The CR rate of each group was 55.6%(VA), 87.0%(DA), 65.8%(IA), 90.4%(HAA), and 100%(DAV) respectively. Among the patients who received CR, patients in DAV group showed more pronounced decreasing of fusion gene levels (median 1450 fold) than other groups, while VA group had the slightest (median 8.9 fold). As to the survival, the median follow-up time was 15.2 months, and the median overall survival (OS) were not reached in all the groups. In the RUNX1:RUNXT1 fusion subgroup, DAV group showed significantly improved OS and event-free survival (EFS) than other groups, while VA groups was the worst. The median EFS were as follows: 3.5months(VA), not reached(HAA), 10.9months(DA), 7.9months(IA), and not reached(DAV) respectively. Conclusions: Our study demonstrated a promising therapeutic results of DAV regimen, and an unsatisfactory therapeutic results of VA regimen in CBF-AML. CBF-AML patients showed significantly improved CR rate, elimination of fusion genes, OS, and EFS when received intense chemotherapy, especially DAV and HAA regimen, than VA regimen. These results indicated that intense chemotherapy may be an optimal choice for CBF-AML.
A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART) SWOG S1609: The desmoid tumors (cohort 27).
Authors: Young Kwang Chae, Megan Othus, Sandip Pravin Patel, Benjamin Powers, Chung-Tsen Hsueh, Rangaswamy Govindarajan, Silvana Z. Bucur, Liam Il-Young Chung, Christine McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles David Blanke, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2023)

11516 Background: Dual inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors is efficacious in many malignancies, but their potential role in numerous rare solid cancers is yet to be established. Desmoid tumors (DT; fibromatosis) are rare tumors of the soft tissue, and the mainstay of treatment is surgery (Richard Riedel, 2022). The utility of immunotherapy in this group of patients has not been explored. This study presents the first results of ipilimumab and nivolumab used in the DT cohort (#27) of the SWOG S1609 Dual Anti-CTLA-4 &amp; Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint includes objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)). Secondary endpoints include progression-free survival (PFS), overall survival (OS), stable disease (SD) &gt; 6 months, and toxicity. Results: Sixteen evaluable patients (median age 37) with desmoid tumors were analyzed. Location of the tumors are: 8, abdomen; 3, lower limb: 2, upper limb; 2, pelvis; and 1, neck. ORR was 18.8% with 3 patients attaining PR: 40% regression with ongoing duration of response (DoR) at over 30+ months; 83% regression (PFS 16 months); and 71% regression (PFS of 8.4 months). Of note, 3 patients had SD (3/16, 18.8%) with some shrinkage of the tumors and a durable response; 23% regression with PFS of 1820+ days; 6% regression with PFS of 902 days; 1% regression with PFS of 1147+ days. Overall clinical benefit rate (CBR; no progression &gt; 6 months) was 62.5%. The median PFS was 17.9 months, 6-month PFS 69%, 1-year PFS 62%. All patients were alive at 1 years; median OS was not assessable as 14 patients are showing ongoing survival. The most common adverse events were fatigue (43.8%, n = 7), nausea (37.5%, n = 6), hypothyroidism (31.3%, n = 5), diarrhea, hyperthyroidism, headache, and adrenal insufficiency (25%, n = 4 each). There were 8 incidents (50%) of grade 3-4 adverse events. 7 adverse events led to discontinuation. There were no grade 5 adverse events. Conclusions: Ipilimumab plus nivolumab in treatment of desmoid tumors resulted in an ORR of 18.8% and CBR of 62.5% with durable responses seen. This is the first prospective study demonstrating efficacy of the combination in this rare disease. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies in desmoid tumors are needed. Clinical trial information: NCT02834013 .